Esters are an important class of compounds that are encountered in various roles in all areas of synthetic organic chemistry. General methods of preparing esters start from carboxylic acids which are directly condensed with alcohol using acid catalysis (Fischer esterification). These prior esterification methods, in spite of their utility, suffer from several environmental drawbacks. Fischer esterification is an equilibrium process typically catalyzed by strong, corrosive, mineral acids (e.g., pKa<0). The water generated in the reaction has to be continuously removed by azeotroping or by use of a dehydrative agent or its role countered by use of a large excess of alcohol. Commonly used alcohols, such as methanol and ethanol, can generate genotoxic alkyl sulphates. Acylation and alkylation are inherently polluting because of salt generation, the use of toxic catalysts and reagents and use of chlorinated solvents.
In recent years chemists have looked to other ester preparation approaches that can be less polluting and more environmentally friendly. Dimethylcarbonate (DMC) has gained prominence as a “green” reagent in either acid- or base-catalyzed methylation or methoxycarbonylation of anilines, phenols, active methylene compounds and carboxylic acids. The attraction of DMC lies in the fact that it is non-toxic and gives rise only to CO2 and methanol (recoverable) as the byproducts.
Several groups have proposed different approaches of using DMC in base-catalyzed methylation or methoxycarbonylation of anilines, phenols, active methylene compounds and carboxylic acids. Others have proposed a chemoselective process for the esterification of carboxylic acids under mild (˜80°-90° C.) and solvent-free conditions using DMC and diethylcarbonate (DEC) under acid catalysis. (See, Vamsi V. Rekha et al., “A Simple, Efficient, Green, Cost Effective and Chemoselective Process for the Esterification of Carboxylic Acids,” ORGANIC PROCESS RESEARCH & DEVELOPMENT, Vol. 13, No. 4, 769-773 (2009).) The process acquires the use of strong acids (i.e., pKa<0) such as H2SO4), or p-toluenesulfonic acid (PTSA), or mild acids such as m-toluic acid (MTA), which requires a downstream neutralization step prior to purification.
Another issue with current esterification reactions of organic acids with DMC is that they are often performed in dimethylformamide (DMF), which can be troublesome in post-synthesis downstream processing and purification, because of DMF's high boiling point (e.g., ˜153° C.) and propensity to decompose overtime, which can lead to formation of highly toxic and reactive dimethylamine. This contamination of the desired ester products can be costly and harmful.
In view of the foregoing disadvantages a new process of esterification is needed, that can eliminate or minimize the issues associated with esterification reactions that depend on an extrinsic catalyst.